Introduction

Embryonic hepatic bud formation.

This section of notes gives an overview of how the liver develops. The transverse septum (septum transversum) arises at an embryonic junctional site. The junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac. The junctional region internally is where the foregut meets the midgut. The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form. Arises at embryonic junction (septum transversum): externally is where ectoderm of amnion meets endoderm of yolk sac and internally is where the foregut meets the midgut. Mesenchymal structure of transverse septum provides a support within which both blood vessels and liver begin to form in the underlying splanchnic mesoderm.

In the early embryo, the liver and heart grow rapidly forming obvious external swellings on the ventral embryo surface. The liver's initial embryonic function is mainly cardiovascular. Firstly, as a vascular connection between the developing placental vessels to the heart. Secondly, as a haemopoietic tissue where blood stem cells reside before bone marrow development.

Some Recent Findings

Human Liver (week 8, GA week 10)

The fate of the vitelline and umbilical veins during the development of the human liver[1] "Differentiation of endodermal cells into hepatoblasts is well studied, but the remodeling of the vitelline and umbilical veins during liver development is less well understood. We compared human embryos between 3 and 10 weeks of development with pig and mouse embryos at comparable stages, . ...We found no evidence for large-scale fragmentation of embryonic veins as claimed by the 'vestigial' theory. Instead and in agreement with the 'lineage' theory, the vitelline and umbilical veins remained temporally identifiable inside the liver after being engulfed by hepatoblasts. In agreement with the 'hemodynamic' theory, the left-right shunts develop de novo."

Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver[2] "Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. ....In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis.

Dynamic signaling network for the specification of embryonic pancreas and liver progenitors[3] Studies of the formation of pancreas and liver progenitors have focused on individual inductive signals and cellular responses. Here, we investigated how bone morphogenetic protein, transforming growth factor-beta (TGFbeta), and fibroblast growth factor signaling pathways converge on the earliest genes that elicit pancreas and liver induction in mouse embryos. The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and two permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGFbeta pathway."

Notch signaling controls liver development by regulating biliary differentiation[4] "In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate."

More recent papers

This table shows an automated computer PubMed search using the listed sub-heading term.

Therefore the list of references do not reflect any editorial selection of material based on content or relevance.

References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Bile duct morphology as earlier stage. Common bile duct empties at the level of the proximal duodenum.

Portal vein arises from the joining of the splenic vein and the superior mesenteric vein. At the level of the hepatic hilum, portal vein divides into two branches, right portal branch (420 µm in diameter) and left portal branch (540 􏰁m in diameter). Right portal branch gives rise to a thin branch to the caudate lobe. Ventral branch gives rise to segmental portal veins (VIII and V). Dorsal branch gives rise to the segmental portal veins (VI and VII).

Ductus venosus connects the initial portion of the left portal vein to the inferior vena cava just upstream from the hepatic vein afferents.

Development

Stage 13

The images below link to larger cross-sections of the mid-embryonic period (end week 4) stage 13 embryo starting just above the level of the liver and then in sequence through the liver to the level of the stomach. Note the relative position of the liver with respect to the abdominal cavity, the gall bladder and the heart.

The transverse septum differentiates to form the hepatic diverticulum and the hepatic primordium, these two structures together will go on to form different components of the mature liver and gall bladder. At this stage large vascular channels can be seen coursing through the liver primordium.

Stage 22

The links shown in the table below are to specific features shown on the Human embryo (stage 22) Liver and Ductus Venosus virtual slide. See also notes on Liver Development

Clicking the text will open the slide at a detailed view with the structure generally located in the centre of the view. The slide then can also be zoomed out from the set magnification using the controls in the upper left or the mouse.

The links shown in the table below are to specific features shown on the Human embryo (stage 22) Liver and Ductus Venosus virtual slide. See also notes on Liver Development

Clicking the text will open the slide at a detailed view with the structure generally located in the centre of the view. The slide then can also be zoomed out from the set magnification using the controls in the upper left or the mouse.

The images below link to larger cross-sections of the end of the embryonic period (week 8) stage 22 embryo starting just above the level of the liver and then in sequence through the entire liver. (Note the sections are viewed from below, LR axis is reversed)

The rapidly developing liver also forms a visible surface bulge on the embryo directly under the heart bulge. The liver now occupies the entire ventral body cavity with parts of the gastrointestinal tract and urinary system "embedded" within its structure. Note in this image the large central ductus venosus.

Selected Stage 22 Images

E3 Overview of liver region for selected high power views shown below. Note the position and size of the developing liver spanning the entire abdomen and within the liver the large central ductus venosus.

Ductal Plate

The ductal plate is a primitive biliary epithelium which develops in mesenchyme adjacent to portal vein branches (periportal hepatoblasts). During liver development it is extensively reorganised (ductal plate remodelling) within the developing liver to form the intrahepatic bile ducts (IHBD). If remodelling does not occur, leading to excess of embryonic bile duct structures in the portal tract, these developmental abnormalities are described as "ductal plate malformation" (DPM).

Ductal Plate Malformations

Bile Secretion

The epithelial cells that line the bile ducts are called cholangiocytes.

The pathway below describes the production and passage of bile for final excretion into the duodenum:

hepatocytes produce bile

secreted into bile canaliculi

connected to intrahepatic bile ducts

intrahepatic bile ducts connect to the hepatic duct

then the cystic duct for storage in the gallbladder

then the common bile duct into the duodenum

The term extrahepatic bile ducts (EHBDs) is used to describe the hepatic, cystic, and common bile ducts.

The developing bile ducts express VEGF while hepatoblasts express angiopoietin-1, these two signals are thought to regulate arterial vasculogenesis and remodeling of the hepatic artery respectively.[13]

Liver Blood Flow

Dual blood supply of the liver merges upon entry into the liver lobule at the portal field.

branches of the portal vein

branches of the hepatic artery

The blood flows along the sinusoid and exits at the central vein.

Hepatocytes

Adult Liver sinusoid structure

These are the adult functional cells forming the majority of the liver (80% of the cells).

Histology

Abnormalities

Congenital absence of the portal vein (CAPV) - a rare abnormality where the intestinal and splenic venous drainage bypass the liver and drain directly into the systemic veins through various porto-systemic shunts.

Terms

allantois - An extraembryonic membrane, endoderm in origin extension from the early hindgut, then cloaca into the connecting stalk of placental animals, connected to the superior end of developing bladder. In reptiles and birds, acts as a reservoir for wastes and mediates gas exchange. In mammals is associated/incorporated with connecting stalk/placental cord fetal-maternal interface.

amnion - An extra-embryonic membrane, ectoderm and extraembryonic mesoderm in origin, also forms the innermost fetal membrane, that produces amniotic fluid. This fluid-filled sac initially lies above the trilaminar embryonic disc and with embryoic disc folding this sac is drawn ventrally to enclose (cover) the entire embryo, then fetus. The presence of this membane led to the description of reptiles, bird, and mammals as amniotes.

amniotic fluid - The fluid that fills amniotic cavity totally encloses and cushions the embryo. Amniotic fluid enters both the gastrointestinal and respiratory tract following rupture of the buccopharyngeal membrane. The late fetus swallows amniotic fluid.

buccal - (Latin, bucca = cheek) A term used to relate to the mouth (oral cavity).

bile salts - Liver synthesized compounds derived from cholesterol that function postnatally in the small intestine to solubilize and absorb lipids, vitamins, and proteins. These compounds act as water-soluble amphipathic detergents.

buccopharyngeal membrane - (oral membrane) (Latin, bucca = cheek) A membrane which forms the external upper membrane limit (cranial end) of the early gastrointestinal tract (GIT). This membrane develops during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane lies at the floor of the ventral depression (stomodeum) where the oral cavity will open and will breakdown to form the initial "oral opening" of the gastrointestinal tract. The equivilent membrane at the lower end of the gastrointestinal tract is the cloacal membrane.

cloacal membrane - Forms the external lower membrane limit (caudal end) of the early gastrointestinal tract (GIT). This membrane is formed during gastrulation by ectoderm and endoderm without a middle (intervening) layer of mesoderm. The membrane breaks down to form the initial "anal opening" of the gastrointestinal tract.

cholangiocytes - epithelial cells that line the intra- and extrahepatic ducts of the biliary tree. These cells modify the hepatocyte-derived bile, and are regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules.

coelom - Term used to describe a space. There are extraembryonic and intraembryonic coeloms that form during vertebrate development. The single intraembryonic coelom will form the 3 major body cavities: pleural, pericardial and peritoneal.

crypt of Lieberkühn - (intestinal gland, intestinal crypt) intestinal villi epithelia extend down into the lamina propria where they form crypts that are the source of epithelial stem cells and immune function.

foregut - The first of the three part/division (foregut - midgut - hindgut) of the early forming gastrointestinal tract. The foregut runs from the buccopharyngeal membrane to the midgut and forms all the tract (esophagus and stomach) from the oral cavity to beneath the stomach. In addition, a ventral bifurcation of the foregut will also form the respiratory tract epithelium.

galactosemia - Metabolic abnormality where the simple sugar galactose (half of lactose, the sugar in milk) cannot be metabolised. People with galactosemia cannot tolerate any form of milk (human or animal). Detected by the Guthrie test.

gastrula - (Greek, gastrula = little stomach) A stage of an animal embryo in which the three germ layers (Endoderm/ Mesoderm/Ectoderm) have just formed.

gastrulation - The process of differentiation forming a gastrula. Term means literally means "to form a gut" but is more in development, as this process converts the bilaminar embryo (epiblast/hypoblast) into the trilaminar embryo (Endoderm/ Mesoderm/Ectoderm) establishing the 3 germ layers that will form all the future tissues of the entire embryo. This process also establishes the the initial body axes. (More? Gastrulation)

Guthrie test - (heel prick) A neonatal blood screening test developed by Dr Robert Guthrie (1916-95) for determining a range of metabolic disorders and infections in the neonate. (More? Guthrie test)

hindgut - The last of the three part/division foregut - midgut - hindgut) of the early forming gastrointestinal tract. The hindgut forms all the tract from the distral transverse colon to the cloacal membrane and extends into the connecting stalk (placental cord) as the allantois. In addition, a ventral of the hindgut will also form the urinary tract (bladder, urethra) epithelium.

intraembryonic coelom - The "horseshoe-shaped" space (cavity) that forms initially in the third week of development in the lateral plate mesoderm that will eventually form the 3 main body cavities: pericardial, pleural, peritoneal. The intraembryonic coelom communicates transiently with the extraembryonic coelom.

neuralation - The general term used to describe the early formation of the nervous system. It is often used to describe the early events of differentiation of the central ectoderm region to form the neural plate, then neural groove, then neural tube. The nervous system includes the central nervous system (brain and spinal cord) from the neural tube and the peripheral nervous system (peripheral sensory and sympathetic ganglia) from neural crest. In humans, early neuralation begins in week 3 and continues through week 4.

neural crest - region of cells at the edge of the neural plate that migrates throughout the embryo and contributes to many different tissues. In the gastrointestinal tract it contributes mainly the enteric nervous system within the wall of the gut responsible for peristalsis and secretion.

pharynx - uppermost end of gastrointestinal and respiratory tract, in the embryo beginning at the buccopharyngeal membrane and forms a major arched cavity within the phrayngeal arches.

somitogenesis The process of segmentation of the paraxial mesoderm within the trilaminar embryo body to form pairs of somites, or balls of mesoderm. A somite is added either side of the notochord (axial mesoderm) to form a somite pair. The segmentation does not occur in the head region, and begins cranially (head end) and extends caudally (tailward) adding a somite pair at regular time intervals. The process is sequential and therefore used to stage the age of many different species embryos based upon the number visible somite pairs. In humans, the first somite pair appears at day 20 and adds caudally at 1 somite pair/4 hours (mouse 1 pair/90 min) until on average 44 pairs eventually form.

splanchnic mesoderm - Gastrointestinal tract (endoderm) associated mesoderm formed by the separation of the lateral plate mesoderm into two separate components by a cavity, the intraembryonic coelom. Splanchnic mesoderm is the embryonic origin of the gastrointestinal tract connective tissue, smooth muscle, blood vessels and contribute to organ development (pancreas, spleen, liver). The intraembryonic coelom will form the three major body cavities including the space surrounding the gut, the peritoneal cavity. The other half of the lateral plate mesoderm (somatic mesoderm) is associated with the ectoderm of the body wall.

stomodeum - (stomadeum, stomatodeum) A ventral surface depression on the early embryo head surrounding the buccopharyngeal membrane, which lies at the floor of this depression. This surface depression lies between the maxillary and mandibular components of the first pharyngeal arch.